Biomedical subjects

J H Linehan

Publications and source records attributed to J H Linehan.

At least 37 records · Page 2Linked to original sources

PubMed1994

Impact of parallel heterogeneity on a continuum model of the pulmonary arterial tree.

Model arterial trees were constructed following rules consistent with morphometric data, Nj = (Dj/Da)-beta 1 and Lj = La(Dj/Da)beta 2, where Nj, Dj, and Lj are number, diameter, and length, respectively, of vessels in the jth level; Da and La are diameter and length, respectively, of the inlet artery, and -beta 1 and beta 2 are power law slopes relating vessel number and length, respectively, to vessel diameter. Simulated heterogeneous trees approximating these rules were constructed by assigning vessel diameters Dm = Da[2/(m + 1)]1/beta 1, such that m-1 vessels were larger than Dm (vessel length proportional to diameter). Vessels were connected, forming random bifurcating trees. Longitudinal intravascular pressure [P(Qcum)] with respect to cumulative vascular volume [Qcum] was computed for Poiseuille flow. Strahler-ordered tree morphometry yielded estimates of La, Da, beta 1, beta 2, and mean number ratio (B); B is defined by Nk + 1 = Bk, where k is total number of Strahler orders minus Strahler order number. The parameters were used in P(Qcum) = Pa [formula: see text] and the resulting P(Qcum) relationship was compared with that of the simulated tree, where Pa is total arterial pressure drop, Q is flow rate, Ra = (128 microLa)/(pi D4a (where mu is blood viscosity), and Qa (volume of inlet artery) = 1/4D2a pi La. Results indicate that the equation, originally developed for homogeneous trees (J. Appl. Physiol. 72: 2225-2237, 1992), provides a good approximation to the heterogeneous tree P(Qcum).

Algorithms↗

PubMed1994

Edema development and recovery in neurogenic pulmonary edema.

We determined the time course of changes in extravascular lung water (EVLW) that occur after massive sympathetic activation produced by intracisternal veratrine administration in chloralose-anesthetized dogs. Three groups of dogs were studied. In the first group (n = 9), acute increases in EVLW (occurring within minutes) were determined both by measuring extravascular thermal volume and by gravimetric analysis. In the second (n = 6) and third (n = 7) groups, changes in EVLW were followed for 2-3 h after veratrine administration. Extravascular thermal volume was measured in the second group. In the third group, right atrial injections of a vascular indicator (125I-labeled serum albumin) and an extravascular indicator (3HOH) were made while blood was sampled from the pulmonary artery (PA) and left atrium, and EVLW was determined by deconvolution of the left atrial and PA concentration-time curves. Indicator-dilution and gravimetric EVLW increased acutely only in dogs in which PA pressure exceeded 60 Torr, with two- to four-fold increases in EVLW being observed in dogs that developed the highest PA pressures (maximum 94 Torr). Thus, severe edema can develop rapidly after massive sympathetic nervous system activation but requires extreme degrees of pulmonary hypertension. In several dogs after the acute increase in EVLW associated with the pulmonary hypertension, the indicator-dilution EVLW decreased with time. These decreases appear to effect clearance of edema fluid rather than alterations in perfusion.

Animals↗

PubMed1994

Reduction and accumulation of methylene blue by the lung.

We studied the disposition of methylene blue added to the perfusate passing through isolated perfused rabbit lungs. Experiments were carried out in a recirculating or single-pass mode, the latter with either a steady infusion or bolus injection of the dye in its blue oxidized form (MB+) or in its colorless reduced leukomethylene blue form (MBH). The recirculation experiments revealed that the dye was taken up by the lungs and that a substantial fraction (approximately 16%) of the MB+ entering the pulmonary artery was reduced before it emerged from the pulmonary veins. Sequestration of the dye by the lungs was a relatively slow process, and the blue color of the lungs at a time when there was little dye left in the perfusate suggests that much of the sequestered dye was in the oxidized form. The results from the single-pass bolus and steady infusion experiments suggest that MBH diffuses rapidly between perfusate and tissue and that it is more soluble in the tissue than in the perfusates used in the study. In this context, the concept of "solubility" includes the impact of the rapidly equilibrating associations of the dye with the perfusate albumin and tissue components. The observed characteristics of the disposition of the methylene blue within the lungs and the rapid rate of its reduction on passage through the lungs suggest that it may be useful to evaluate the possibility that changes in reduction, uptake, and/or sequestration rates may reflect alterations in the metabolic function of the lungs.

Animals↗

PubMed1994

The vascular site of action of hypoxia in the neonatal pig lung.

To determine the vascular site(s) of action of hypoxia in the neonatal pig, isolated lungs were perfused at a constant flow rate and left atrial pressure; arterial, venous, and double occlusions were performed. The distribution of the total pulmonary vascular resistance and the total dynamic vascular compliance were calculated using a model of the pulmonary circulation consisting of upstream, central, and downstream compliances and resistances upstream and downstream of central compliance. In addition, the static vascular compliance was measured by venous followed by arterial occlusion, and the total vascular volume was measured by dye-dilution. In this preparation during control conditions alveolar PO2 = 12 +/- 2 kPa), total pulmonary vascular resistance was nearly evenly divided between resistance upstream and downstream of double occlusion pressure and total dynamic vascular compliance was concentrated mainly in the central compliance (7% upstream compliance, 82% central compliance, and 11% downstream compliance). Hypoxia (alveolar PO2 = 4 +/- 1 kPa) increased both resistance upstream of double occlusion pressure (p < 0.005) and resistance downstream of double occlusion pressure (p < 0.02) and decreased central compliance (p < 0.005). Hypoxia also decreased total pulmonary blood volume (p < 0.02). These results suggest that in the pulmonary vasculature of the neonatal pig, hypoxia results mainly in 1) arterial constriction as evidenced by a large increase in upstream resistance and a decrease in total pulmonary blood volume and 2) a smaller but significant venous constriction. This venous constriction may have implications in the pathogenesis and therapy of pulmonary vascular diseases associated with hypoxia such as postasphyxial lung disease and bronchopulmonary dysplasia.

Animals↗

PubMed1993

Model-free numerical deconvolution of recirculating indicator concentration curves.

This paper investigates two model-free methods for numerical deconvolution of recirculating indicator concentration curves. The two methods, damped least squares and discrete orthogonal polynomial deconvolution, are applied to simulated data to verify the reliability of the algorithms. Both deconvolution methods provide damping that results in estimated transport functions that are smooth and reasonable estimates of the actual simulated transport function. On convolution with the simulated input curve, the estimated transport functions provide good fits to the simulated output curve. In addition, methods for identifying an optimal solution and for truncating the artifactually long oscillatory tails of the estimated transport functions are proposed, which appear to allow for reasonably accurate estimation of the mean transit times and variances of the transport functions as well. When either method was applied to indicator dilution data obtained from the pulmonary artery and left atrium, it was computationally stable while producing transport functions that when convolved with the input concentration curves provided good fits to the output concentration curves. The combined simulation and experimental results suggest that the proposed methods should be useful for estimating circulation transport functions from indicator dilution data.

Algorithms↗

PubMed1993

A distensible vessel model applied to hypoxic pulmonary vasoconstriction in the neonatal pig.

Recently, we presented a simple two-parameter distensible vessel model as a potential tool for characterizing pulmonary vascular pressure vs. flow curves under zone 3 conditions (Linehan et al. J. Appl. Physiol. 73: 987-994, 1992). One parameter, alpha, represents the distensibility of the resistance vessels as the fractional change in vessel diameter per Torr change in pressure, and the other parameter, R0, represents the vascular resistance that would exist if the resistance vessels were at their respective diameters obtained if the vascular pressure were zero. The objective of the present study was to determine whether this distensible vessel model was capable of describing the pressure vs. flow data obtained during hypoxia vasoconstriction and under control conditions in isolated lungs from neonatal pigs. The piglet lungs were perfused with autologous blood, and the pulmonary arterial pressure was measured over a range of flow rates from 15 to 250 ml.min-1 x kg-1 at constant left atrial (3 Torr) pressure. The model provided a reasonable fit to the data under both conditions. Hypoxia resulted in a significant increase in R0, from 0.39 +/- 0.10 Torr.ml-1 x min.kg during control conditions to 1.41 +/- 0.46 Torr.ml-1 x min.kg during hypoxia. alpha was 2.4 +/- 0.4%/Torr under control conditions and 2.0 +/- 0.4%/Torr during hypoxia, but this difference was not statistically significant. The results suggest that the distensible vessel model may be useful for interpreting pressure-flow data in terms of changes in geometry and distensibility of the resistance vessels in response to a vasoconstrictor stimulus such as hypoxia.

Animals↗

PubMed1993

Angiotensin-converting enzyme preferentially hydrolyzes trans isomer of proline-containing substrate.

An analysis of the hydrolysis kinetics of the synthetic angiotensin-converting enzyme (ACE) substrate benzoyl-phenylalanyl-alanyl-proline (BPAP) in the intact lung suggested that 12-15% of the BPAP was in a form that could not be hydrolyzed by ACE in the time course of a single pass through the lungs [C. A. Dawson et al. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H853-H865, 1989]. BPAP has been found to exist as a mixture of cis and trans isomers in a ratio of approximately 14:86 in aqueous solution at equilibrium. Thus, one possible explanation for the incomplete hydrolysis of BPAP on passage through the intact lung is that the trans form is the preferred substrate for ACE. To examine this hypothesis, we measured BPAP hydrolysis by ACE in vitro over a range of ACE concentrations and in the presence and absence of the peptidyl-prolyl cis-trans isomerase cyclophilin. In the presence of a sufficient concentration of ACE and in the absence of cyclophilin, hydrolysis of [3H]BPAP by ACE followed biexponential progress curves, consistent with the hypothesis that the rate of hydrolysis of the majority (approximately 87%) of the substrate is proportional to ACE concentration, whereas the hydrolysis rate of the remaining substrate fraction is independent of enzyme concentration. The addition of cyclophilin resulted in an increase in the ACE-independent rate constant, an effect that was reversed by the cyclophilin inhibitor cyclosporin A. These results suggest that the enzyme-independent rate constant represents the rate of cis-trans isomerization and that the enzyme-dependent rate constant represents the hydrolysis of the trans isomer.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Isomerases↗

PubMed1993

Direct measurement of pulmonary microvascular distensibility.

Pulmonary vascular distensibility has an important influence on pulmonary hemodynamics. Although many measurements of distensibility have been made on large pulmonary vessels, there is less information on microvascular distensibility. We have measured the distensibility of the smallest (< 70-microns-diam) precapillary arterioles and postcapillary venules. Isolated dog lobes, at 2.5 cmH2O transpulmonary pressure, were perfused at low flows, which caused the arteriovenous pressure gradient to be very small and thereby permitted accurate estimation of microvascular pressure. As microvascular pressure was systematically varied between 0 and 30 mmHg, subpleural microvascular diameters were determined from computer-enhanced images obtained by videomicroscopy. Arteriolar and venular distensibilities were not different from each other. The microvascular pressure-diameter relationship was alinear with distensibility coefficients of 1-3% mmHg-1, values that are of the same order of magnitude as previously measured distensibilities of 100- to 1,000-microns-diam canine pulmonary vessels.

Animals↗

PubMed1992

Use of blue dextran for measuring changes in perfused vascular surface area in lungs.

We investigated the uptake and efflux of Blue Dextran in the isolated perfused rabbit lung. Blue Dextran is a high-molecular-weight glucose polymer (original mol wt 2 x 10(6) g/mol) containing covalently bonded Reactive Blue 2 dye (approximately mmol/g dextran). This blue dye is known for its high binding affinity to a wide variety of proteins, with a particularly high affinity for serum albumin. In isolated rabbit lungs perfused with a protein-free perfusate, both bolus injection and recirculation of Blue Dextran revealed a rapid saturable uptake. Once the lungs were loaded with Blue Dextran, efflux of the Blue Dextran accumulated in the lungs could be induced by addition of bovine serum albumin (BSA) to the recirculating perfusate. The amount of BSA-induced efflux of Blue Dextran from the lung was independent of perfusate flow. When the left pulmonary artery was ligated after the lungs had been loaded with Blue Dextran, the dye-induced BSA efflux was only about 50% of normal. Release of the ligature so that both lungs were perfused resulted in efflux of the remaining Blue Dextran. The combination of high airway pressure and low flow also reduced the dye efflux, and the effect was reversed by reducing the airway pressure. With the assumption that the high average molecular weight of Blue Dextran confines this molecule to interaction with proteins on the vascular surface, the results of this study suggest that Blue Dextran uptake and its BSA-induced efflux are proportional to the perfused vascular surface area in the lung.

Animals↗

PubMed1992

Use of diazepam for interpreting changes in extravascular lung water.

Estimates of extravascular lung water volume (Qew) by use of the multiple indicator-dilution method with a hydrophilic indicator such as tritiated water, along with a vascular reference indicator, depend not only on tissue hydration but also on tissue perfusion. Separation of these effects might be facilitated if both hydrophilic and lipophilic indicators were used, with the assumption that the extravascular volume accessible to the lipophilic indicator would be independent of hydration. We found that in isolated perfused dog lung lobes the extravascular volume accessible to the lipophilic amine [14C]diazepam (Qed) was inversely proportional to the albumin concentration of the perfusate. This suggested that while the bolus was in the lungs, only a small fraction of the diazepam was in the aqueous phase of either lung tissue or perfusate. Changing the flow rate over a fairly wide range had little influence on the pattern of the tritiated water or [14C]diazepam effluent concentration curves when time was normalized to the lobar mean transit time. This suggests that the association of the diazepam with both the plasma albumin and the lipoid fraction of the tissue was in very rapid equilibrium on the time scale of a single pass through the lung lobe and that there was little barrier to its diffusion to and from the tissue. When the extravascular water volume was increased by either raising the hydrostatic pressure or instilling saline into the airways, both Qew and Qew/Qed increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗

PubMed1992

Influence of flow on pulmonary vascular surface area inferred from blue dextran efflux data.

Blue dextran (BD), which binds to proteins on the pulmonary endothelial surface and to plasma albumin, was used in isolated perfused dog lung lobe experiments to address the question: do changes in perfusate flow rate cause changes in perfused vascular surface area? When BD was added to a protein-free perfusate under zone 3 conditions at a high flow rate (15.8 +/- 0.7 ml/s), it was adsorbed by the endothelial surface. Then by changing the perfusate entering the lobe to an albumin-containing perfusate, the BD was eluted from the perfused surface by competitive binding to the perfusate albumin. The amount of BD eluted was measured in three experiments. In experiment 1, elution of the BD by the perfusate albumin was initiated after a balloon had been inflated within the lobar arterial tree to occlude a portion of the lobar vascular bed containing BD. Then the balloon was deflated, permitting albumin perfusate to perfuse the previously occluded part of the lobe. In experiment 2, BD elution began at a flow rate of 3 +/- 0.1 ml/s under zone 3 conditions and continued after the high-flow zone 3 conditions were reestablished. In experiment 3, the BD elution began at a flow rate of 4.2 +/- 0.7 ml/s under zone 2 conditions and continued after the high-flow zone 3 conditions were reestablished. Balloon inflation reduced the amount of BD recovered by 43%, demonstrating that a decrease in perfused vascular surface area could decrease BD recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

A fractal continuum model of the pulmonary arterial tree.

The extant morphometric data from the intrapulmonary arteries of dog, human, and cat lungs produce graphs of the log of the vessel number, (N) or length (l) in each level vs. the log of the mean diameter (D) in each level that are sufficiently linear to suggest that a scale-independent self-similar or fractal structure may underlie the observed relationships. These data can be correlated by the following formulas: Nj = a1Dj-beta 1, and lj = a2Dj beta 2, where j denotes the level (order or generation) number measured from the largest vessel at the entrance to the arterial tree to the smallest vessel at the entrance to the capillary bed. With the hemodynamic resistance (R) represented by Rj = 128 microliterj/(Nj pi Dj4) and the vascular volume (Q) by Qj = Nj pi Dj2lj/4, the continuous cumulative distribution of vascular resistance (Rcum) vs. cumulative vascular volume (Qcum) (where Rcum and Qcum represent the total resistance or volume, respectively, upstream from the jth level) can be calculated from [formula: see text] where r = Dj/Dj+1 is a constant independent of j. Analogous equations are developed for the inertance and compliance distributions, providing simple formulas to represent the hemodynamic consequences of the pulmonary arterial tree structure.

Animals↗

PubMed1992

A method for analysis of pulmonary arterial and venous occlusion data.

Recently, we presented a compartmental model of the pulmonary vascular resistance (R) and compliance (C) distribution with the configuration C1R1C2R2C3 (J. Appl. Physiol. 70: 2126-2136, 1991). This model was used to interpret the pressure vs. time data obtained after the sudden occlusion of the arterial inflow (AO), venous outflow (VO), or both inflow and outflow (DO) from an isolated dog lung lobe. In the present study, we present a new approach to the data analysis in terms of this model that is relatively simple to carry out and more robust. The data used to estimate the R's and C's are the steady-state arterial [Pa(0)] and venous [Pv(0)] pressures, the flow rate (Q), the area (A2) encompassed by Pa(t) after AO and the equilibrium pressure (Pd) after DO, and the average slope (m) of the Pa(t) and Pv(t) curves after VO. The following formulas can then be used to calculate the 2 R's and 3 C's: [Pa(0) - Pv(0)]/Q = R1 + R2 = RT, R1C1 congruent to to A2/[Pa(0) - Pd], R1 congruent to [Pa(0) - Pd]/Q, Q/m = C1 + C2 + C3 = CT, and C2 = CT - (RTC1/R2).

Animals↗

PubMed1992

A simple distensible vessel model for interpreting pulmonary vascular pressure-flow curves.

A simple distensible vessel model was developed for the purpose of interpreting the vascular pressure-flow curve in the zone 3 lung. The model-governing equation has two parameters: R0, representing the hemodynamic resistance of the undistended pulmonary vascular bed, and alpha, representing the distensibility of the resistance vessels. To evaluate the model, the governing equation was used in a nonlinear regression analysis of the pressure-flow data from isolated dog lung lobes. The dependency of the estimates of the model parameters in response to changes in perfusate viscosity (hematocrit) was determined. The distensible vessel model provided reasonable fits to the data, and, as predicted, R0, but not alpha, was hematocrit dependent. On the other hand, the traditional linear ohmic-Starling resistor model fit to the same pressure-flow data generally provided fits approaching those of the distensibility model only if the pressure intercept (the mean "critical closing pressure") was allowed to increase with hematocrit. Because the ohmic-Starling resistor concept does not predict a hematocrit dependence of the critical closing pressure, this latter observation is evidence that the distensible vessel model offers an alternative conceptualization of the pulmonary circulation worthy of additional study with respect to the interpretation of experimental pressure-flow data.

Animals↗

PubMed1992

Distensibility of small veins of the dog lung.

To determine the distensibility of the intrapulmonary veins (250-2,900 microns diam) of the dog lung, we obtained X-ray angiograms from isolated lung lobes over a vascular pressure range of approximately 0-30 Torr. Over this pressure range the diameter vs. pressure curves tended to flatten out at the high pressures. In the pressure range of 0-19 Torr, we characterized the vessel distensibility by alpha (the ratio of the slope, beta, of the graph of diameter vs. intravascular pressure to the intercept, Do). The average value of alpha was approximately 1.2%/Torr. There was a weak negative correlation (r = -0.32) between alpha and Do. Infusion of enough norepinephrine to produce approximately 50% increase in total lobar vascular resistance produced a decrease in Do and alpha of approximately 33 and 32%, respectively.

Angiography↗

PubMed1991

A hemodynamic model representation of the dog lung.

The published morphometric data from human, cat, and dog lungs suggest that the power-law relationships between the numbers (Na and Nv) and diameters (Da and Dv) of arteries and veins and between the lengths (La and Lv) and diameters of the arteries and veins could be used as scaling rules for assigning dimensions and numbers to the intrapulmonary vessels of the arterial and venous trees of the dog lung. These rules, along with the dimensions of the extrapulmonary arteries and capillary sheet and the distensibility coefficients of the vessels obtained from the literature, were used to construct a steady-state hemodynamic model of the dog lung vascular bed. The model can be characterized approximately by 15 orders of arteries with Na approximately 2.07 Da-2.58 and 13 orders of veins with Nv approximately 2.53 Dv-2.61. For the intrapulmonary vessels (orders 1-12), La approximately 4.85 Da1.01, and Lv approximately 6.02 Da1.07. The average ratio of the numbers of vessels in consecutive orders is approximately 3.2 for the arteries and veins. These arterial and venous trees are connected by the capillary sheet with an undistended thickness of approximately 3.5 microns and an area of 33 m2. The average distensibility (% increase in diameter over the undistended diameter/Torr increase in transmural pressure) for the model arteries and veins is approximately 2.4%/Torr, and the distensibility of the capillary sheet (% increase in thickness over the undistended thickness/Torr increase in transmural pressure) is approximately 3.6%/Torr. The calculated arterial-capillary-venous volumes and compliances of the model agree well with experimental estimates of these variables in dogs. In addition, the model appears consistent with certain aspects of the pressure-flow relationships measured in dog lungs. The model appears to be a useful summary of some of the available data on pulmonary morphometry and vessel properties. It is anticipated that the model will provide the basis for dynamic modeling of the dog lung in the future.

Animals↗

PubMed1991

Effect of vasoconstriction on longitudinal distribution of pulmonary vascular pressure and volume.

We used an improved version of the low-viscosity bolus method to evaluate longitudinal (arterial-to-venous) differences in the sensitivity of the dog lung lobe vasculature to selected vasoconstrictor stimuli, including hypoxia, and serotonin, histamine, and norepinephrine infusions. This method revealed a bimodal distribution of local vascular resistance vs. cumulative vascular volume under the zone 3 conditions studied. Our interpretation of the two modes of relatively high resistance is that they correspond to high resistance per unit volume segments of the arteries and veins upstream and downstream from the relatively low resistance per unit volume capillary bed. Thus an increase in the height of the upstream and downstream modes of the resistance distribution suggests constriction in small arteries and veins, respectively. Horizontal displacement of the modes along the cumulative volume axis suggests changes in the distribution of volume among the arteries, veins, and capillary bed. By use of these criteria, the results are consistent with the concept that each of the vasoconstrictor stimuli studied had a different longitudinal response pattern. Hypoxia constricted mainly small arteries, whereas serotonin constricted small and large arteries. Histamine constricted large and small veins, and norepinephrine constricted large and small veins and arteries.

Animals↗

PubMed1991

Localization of the sites of pulmonary vasomotion by use of arterial and venous occlusion.

In this study, we present a new approach for using the pressure vs. time data obtained after various vascular occlusion maneuvers in pump-perfused lungs to gain insight into the longitudinal distribution of vascular resistance with respect to vascular compliance. Occlusion data were obtained from isolated dog lung lobes under normal control conditions, during hypoxia, and during histamine or serotonin infusion. The data used in the analysis include the slope of the arterial pressure curve and the zero time intercept of the extrapolated venous pressure curve after venous occlusion, the equilibrium pressure after simultaneous occlusion of both the arterial inflow and venous outflow, and the area bounded by equilibrium pressure and the arterial pressure curve after arterial occlusion. We analyzed these data by use of a compartmental model in which the vascular bed is represented by three parallel compliances separated by two series resistances, and each of the three compliances and the two resistances can be identified. To interpret the model parameters, we view the large arteries and veins as mainly compliance vessels and the small arteries and veins as mainly resistance vessels. The capillary bed is viewed as having a high compliance, and any capillary resistance is included in the two series resistances. With this view in mind, the results are consistent with the major response to serotonin infusion being constriction of large and small arteries (a decrease in arterial compliance and an increase in arterial resistance), the major response to histamine infusion being constriction of small and large veins (an increase in venous resistance and a decrease in venous compliance), and the major response to hypoxia being constriction of the small arteries (an increase in arterial resistance). The results suggest that this approach may have utility for evaluation of the sites of action of pulmonary vasomotor stimuli.

Animals↗